You are on page 1of 28

Quality by Design & Design For Six Sigma

:
Allies in Pharmaceutical Development
ISPE Breakfast Seminar
Toronto: May 12, 2009
Montreal: May 13, 2009

Presented by: Murray Adams
Contact: murray.adams@rogers.com
1-905-796-8514

Operational Excellence Consulting Ltd.

Guidance Documents
¾

ICH and FDA have published several guidance documents
on pharmaceutical development and validation
ƒ

ICH – Q8, Q8(R1), Q9, Q10

ƒ

FDA – Process Validation: General Principles and Practices

¾

Common theme of systematic, science based approach to
obtaining “enhanced” process knowledge and managing risk

¾

Focus for today: Q8(R1) Pharmaceutical Development
ƒ

Quality by Design (QbD)

ƒ

QbD alignment with Design For Six Sigma (DFSS) principles
Copyright Operational Excellence Consulting Ltd. 2009

1

2009 2 .QbD Key Concepts and Principles ¾ Quality cannot be tested into products it must be built in ¾ Enhanced scientific knowledge of products and processes in development can be used to assure product quality ¾ Critical Quality Attributes (CQA) and factors which affect them must be well understood and controlled ƒ Drug substance ƒ Excipients ƒ Intermediates ƒ Drug product Copyright Operational Excellence Consulting Ltd.

2009 3 .QbD Key Concepts and Principles (Cont’d) ¾ Risk assessment should be used throughout development to guide and justify development decisions ¾ Material and process parameters must be linked to CQAs of the finished product ¾ Design space used to define the acceptable limits for operational parameters to assure the product quality ¾ Control strategies implemented to manage risk Copyright Operational Excellence Consulting Ltd.

a.QbD and DFSS Alignment ¾ Ensure quality on the basis of detailed process knowledge ¾ Understanding the relationships between product/process inputs and outputs ¾ ƒ Design of Experiments (DoE) and/or historical regression analysis ƒ Modeling designs produce prediction equations / transfer functions Transfer functions can then be used to perform: ƒ Expected Value Analysis (EVA a.k. Monte Carlo Simulation) ƒ Robust design ƒ Tolerance allocation studies (setting appropriate specifications) Copyright Operational Excellence Consulting Ltd. 2009 4 .

g. Parameters e. X3) Y2 Copyright Operational Excellence Consulting Ltd. outputs and interactions Transfer Functions Inputs X1 Outputs e.What’s DoE ? ¾ Purposefully changing settings of process inputs (X’s) in order to observe the effect on process outputs (Y’s or CQA’s). X2.g. 2009 5 . ¾ Changing multiple inputs to produce an equation which describes the relationships between inputs. Materials Y1 = f1 (X1.g. Environmental Y1 Process Y2 = f2 (X1. X2. X3) X2 X3 e.

cost) which are affected by inputs ¾ Interactions – combination effect when the effect of one factor depends upon the setting of another factor ¾ Levels – the number of settings evaluated for each factor ¾ Experimental Run – a trial conducted using a carefully chosen combination of settings for each factor Copyright Operational Excellence Consulting Ltd. X’s – variables which if changed or uncontrolled will affect one or more responses ¾ Outputs.DOE Terminology ¾ Inputs. Factors. 2009 6 . Y’s – metrics of interest (quality. cycle time. performance. Responses.

experience ¾ Map the process at a relatively high level (8 – 12 steps) ¾ Cause and Effect Analysis (a. Fishbone / Ishikawa diagram) ¾ Risk assessment – Failure Mode and Effects Analysis (FMEA) ƒ Identify risk areas with materials and process parameters ƒ Which factors and parameters must be controlled? Copyright Operational Excellence Consulting Ltd.k.a. literature search. 2009 7 .Finding the “Critical Few” ¾ Before conducting experiments we must identify the most important factors affecting our process ƒ Find the “critical few among the trivial many” ƒ Prior knowledge.

Cause & Effect Example Method Measurement Machine (X) Pre-compression (X) Blend Time (X) Main Compression (C) Test method (X) Lubrication Time (C) SOP / PBR (X) Compression Speed (C) Punch Size / Shape Dissolution Rate (C) Avicel Grade (N) Relative Humidity (N) Experience (X) Mg Stearate Mesh (C) Temperture (C) Training (X) API PSD Manpower Materials C = Constant N = Noise X = Experimental Factor Environment Copyright Operational Excellence Consulting Ltd. 2009 8 .

calculate PRPN Copyright Operational Excellence Consulting Ltd. assign corrective actions.FMEA Example 1. Probability of occurrence? (1 to 5) 3. Calculate RPN = Sev * Occ * Det 7. Probability of escaped detection (1 to 5) Calculate RPN. What are the consequences? 5. Steps / Components Product Function / or Purpose Process Failure Mode Failure Effects S E V Causes Controls D E T R P N Actions 6. What controls are in place today? 9. How could it fail to do this? 4. What’s the intended function or purpose? Plans P S P O P D p r p n 10. prioritize. 2009 9 . How bad is it? (1 to 5) ¾ O C C 8. List all causes leading to failure 2.

Spec .FMEA Examples Formulation Components ¾ Formulation Function Component Failure Mode Failure Effects S E V Drug Substance Active Poor bioavailability Reduced effectiveness Ingredient too little release 5 Magnesium Stearate Lubricant Over lubricated Poor bioavailability (reduced effectiveness) 5 Under lubricated ¾ Causes O C C Controls Incorrect Particle PSD Spec & test 3 Size Distribution method Wrong mesh size .Confirm PSD spec appropriate Actions 2 . 2009 Actions Plans 10 .Confirm spec 1 1 .Spec .None Process Steps Process Step Lubrication Blending Purpose Lubricate granules Failure Mode Over lubricated Failure Effects Under lubricated Picking S E V Controls D E T R P N .Confirm spec 3 12 . May 25 .None .too small 5 Content too high 2 Content too low D E T R P N 4 .Confirm spec 2 Blended too little 2 Copyright Operational Excellence Consulting Ltd.MSA on test method 60 .Spec 1 10 .Spec 1 1 5 2 Causes O C C Poor bioavailability Blended too 4 (reduced effectiveness) much 2 Tablet picking Plans Fred.Timer on blender 3 24 .

intervals. P/Tol. ¾ Measurement System Analysis (MSA) ¾ ¾ ƒ How big is the measurement error? ƒ Accuracy.Data Collection ¾ The knowledge gained in a DoE is only as good as the data we collect for the analysis. 2009 11 . other)? ƒ Is everyone collecting the samples in the same way? What about PAT’s? (Process Analytical Technologies) Copyright Operational Excellence Consulting Ltd. P/Tot Sampling plan ƒ What kind of data are we collecting (continuous or discrete)? ƒ How big a sample do we need? ƒ Is the sample representative? ƒ How are we going to collect the samples? (random. reproducibility. repeatability.

sequence of pictures showing the evolution of the process Allows continuous. a Movie ¾ ¾ Conventional analytical testing provides “snapshots” of quality attributes at various points in time Traditionally we test the finished product at the end of the process + Beginning ¾ ¾ + Middle End PATs can provide real time. 2009 End 12 .Snapshots vs. or near real time. “real time quality assurance” Beginning Continuous Monitoring Copyright Operational Excellence Consulting Ltd.

graphs and data reproduced with permission from Patheon Inc. 2009 Sensor B25 Mean Overall Mean 13 %RSD (Across Sensors) 4.5% 3.0% 4.Which process is yours? “Textbook” 380 Sensor 1 360 Sensor 3 340 2 320 1/2 (Ws /m K) Thermal Effusivity 400 300 Sensor 4 How much do we really know about what’s going on inside the blender? 280 260 240 220 200 0 3 6 9 12 15 18 21 24 27 30 “Variable” Blend Time (minutes) Thermal Effusivity vs Blend Time 410 5.5% 370 2.5% 340 0.0% 350 0.5% 360 1.0% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Time (Minutes) %RSD Sensor B23 Sensor B18 Copyright Operational Excellence Consulting Ltd. and Mathis Instruments 3.0% 380 2.5% 400 Effusivity 390 *Tables.0% 1.0% .

2009 14 .Types of DoE Designs Screening Designs Modeling Designs ¾ Typically 6 – 11 factors ¾ Typically 2 – 5 factors ¾ Many factors in few runs ¾ ¾ Narrow the focus Prediction equation (Transfer function) ¾ 2 or 3 levels ¾ Optimization. robust design. tolerance allocation ¾ 2 or 3 levels Examples Examples ¾ Taguchi L12 (or PB12) ¾ Full / Fractional Factorial ¾ Taguchi L18 (3 levels) ¾ Central Composite Design ¾ PB 20 ¾ Box Behnken ¾ Fractional Factorials Copyright Operational Excellence Consulting Ltd.

2009 15 S . variation.12 .2 .11 .9 .L12 Design Matrix Factor A B Blend Time (Min) Row # 1 2 3 4 5 6 7 8 9 10 11 12 5 5 5 5 5 5 15 15 15 15 15 15 C Lubrication Time (Min) 2 2 2 5 5 5 2 2 2 5 5 5 D E F G Mg Pre-comp Main Comp Press Stearate API PSD Force Force (KN) Speed Mesh (KN) -1 2 5 30 2000 -1 2 5 40 5000 1 5 10 30 2000 -1 5 10 30 5000 1 2 10 40 2000 1 5 5 40 5000 1 5 5 30 5000 1 2 10 40 5000 -1 5 10 40 2000 1 2 5 30 2000 -1 5 5 40 2000 -1 2 10 30 5000 Dissolution Y1 Y2 Y3 ---- Y12 Y bar Random Order = 4 .3 . both or neither ¾ Check up to 11 factors in 12 runs ¾ High level information on main effects only ¾ No information on interactions ¾ Possible to monitor multiple responses Copyright Operational Excellence Consulting Ltd.7 .6 .5 .10 ¾ Identify factors affecting response(s) average.8 .1 .

all 2 way interactions.4 .8 .3 .6 ¾ Full Factorial designs produce prediction equation / transfer function describing relationship between factors and the response(s) ¾ Main effects of 3 factors..2 .. 2009 16 .1 .- Y12 Y bar S 30 40 30 40 30 40 30 40 Random Order = 7 .5 ..23 Full Factorial Example Factor A API PSD (d50) Row # 1 2 3 4 5 6 7 8 B Blend Time 2 2 2 2 5 5 5 5 Dissolution C Main Comp Force (KN) 10 10 15 15 10 10 15 15 Y1 Y2 Y3 . 3 way interaction ¾ Process optimization ¾ Multiple response optimization Copyright Operational Excellence Consulting Ltd.

k. 2009 17 .Transfer Functions (a.a. Prediction Equations) ¾ The transfer function is a equation which mathematically describes the relationship between the process inputs and outputs ¾ This empirical model is extremely valuable knowledge ¾ ƒ Process optimization ƒ Robust design ƒ “What if” scenarios ƒ Setting specifications 2 level designs Y = b0 + b1X1 + b2X2 + b3X1X2 …… ¾ 3 level designs Y = b0 + b1X1 + b2X2 + b3X1X2 + b4X12+ b5X22 …… Copyright Operational Excellence Consulting Ltd.

” ¾ Translation – what combination(s) of input settings will meet the specifications for the output(s)? ¾ Multiple response optimization determines the optimum set of conditions to meet specs of 2 or more outputs simultaneously ¾ “Weighting” the outputs provides opportunity to allow for relative importance in “trade-off” situations Copyright Operational Excellence Consulting Ltd.Design Space ¾ Definition of Design Space according to ICH Q8: ƒ “The multidimensional combination and interaction of input variables that have been demonstrated to provide assurance of quality. 2009 18 .

0 2.2 3.0 4.8 3.4 3.0 20 23 26 28 31 34 37 39 42 45 48 51 53 56 59 62 64 67 70 X1 Copyright Operational Excellence Consulting Ltd.1 2.1 1.3 4. 2009 X1 19 .9 1.0 5.1 3.0 20 23 26 28 31 34 37 39 42 45 48 51 53 56 59 62 64 67 70 Out of Spec X2 1.6 2.0 2.3 2.7 1.2 X2 3.6 4.6 2.4 3.2 1.8 4.4 1.4 1.7 3.9 3.9 1.7 1. dissolution (Y1) and dosage uniformity (Y2) ¾ There may be two inputs (X1 and X2) which are important to both outputs ¾ Which combinations of X1 and X2 are acceptable? Y 1 = dissolution In spec Y 2 = dosage uniformity 5.3 4.Design Space Example ¾ Consider two Outputs – e.1 4.2 1.8 2.g.3 2.6 4.8 4.7 3.9 3.

Design Space Example (Cont’d) ¾ Which combination(s) of X1 and X2 will meet both the dissolution and dosage uniformity specifications? Y 2 = dosage uniformity Y 1 = dissolution X2 X1 Copyright Operational Excellence Consulting Ltd. 2009 X2 X1 20 .

Monte Carlo Simulation) ¾ Unfortunately many inputs are not constants! ¾ EVA applies the distribution of inputs to the transfer functions to predict output distribution X1 Y1 = b0 + b1X1 + b2X2 + b3X1X2 X2 X3 Y1 Process Y2 = b7 + b4X1 + b5X2 + b6X1 Copyright Operational Excellence Consulting Ltd.k.Expected Value Analysis (a.a. 2009 2 Y2 21 .

2009 22 .Robust Design Studies ¾ Helps to identify conditions which make the process tolerant of variation of certain inputs which are difficult or costly to control X X 1 2 Process Process Y 1 X 3 ¾ Initial settings produce outputs which are sometimes out of spec ¾ Shifting input average settings may achieve the same average response but reduce the output variation even though the variation of the inputs remains the same Copyright Operational Excellence Consulting Ltd.

but…. we think tightening input specs will improve the process..Tolerance Allocation ¾ Determines the affect of input variation on the response. ¾ How much would the process improve if we tightened the input spec? X X 1 2 Process Process Y 1 X 3 ¾ Intuitively. so let’s choose the best option ƒ We might find that it’s possible to relax some specs with no ill effects! Copyright Operational Excellence Consulting Ltd. 2009 23 . ƒ Do all inputs have the same amount of influence? ƒ Tighter specs often cost more money.

PBRs. RM specs. Deputy Director. production process to support post-approval distribution. Famulare. facilities.” (1. testing. maintenance etc. process limits. a manufacturer is expected to have accumulated enough data and knowledge about the commercial 1.Control Strategies ¾ SOPs. training programs help to ensure consistency ƒ ¾ Policies. FMEA – “living document” updated throughout product life cycle ƒ Investigate problems and implement corrective actions ¾ Effective transfer of process knowledge from development to production (Tech Transfer) ¾ Process Qualification – confirm design is functional as predicted ƒ “Before commercial distribution begins. Office of Compliance FDA/CDER) Copyright Operational Excellence Consulting Ltd. Joseph C. 2009 24 .

2009 25 .Control Strategies (Cont’d) ¾ Extensive testing (at least initially) to increase data base of knowledge ¾ Control charts alert us to “abnormal” conditions and trends ¾ PATs can be used to monitor and control some critical process steps in “real time” ¾ On-going monitoring provides opportunity for process improvement as more data is accumulated ƒ Historical regression analysis ¾ Annual product reviews ¾ Change Control – ensure data available to support modifications Copyright Operational Excellence Consulting Ltd.

2009 26 .Some Benefits of QbD & DFSS ¾ Assures the quality of product and reliable delivery of its intended performance ¾ Identifies critical controls and potential areas of risk early in the product life cycle (development) ƒ ƒ reduces / eliminates need for significant post approval changes minimizes cost of change ¾ Helps to ensure efficient use of resources. both before and after product launch ¾ “Enhanced” product/process understanding provides opportunities for “more flexible regulatory approaches” ƒ ƒ ƒ risk-based regulatory decisions (reviews and inspections) ease of process improvement within the approved design space real-time QC / reduced end-product release testing Copyright Operational Excellence Consulting Ltd.

com Bus. Email: murray.adams@rogers. Tel: 1-905-796-8514 Copyright Operational Excellence Consulting Ltd.Q&A Presented by: Murray Adams Operational Excellence Consulting Ltd. 2009 27 .